Asenapine (compound trans-(I)) is the international commonly accepted non-proprietary name for trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole, and has an empirical formula of C17H16NOCI and a molecular weight of 285.77. The molecule has two chiral centers but has been developed as the racemic mixture of the trans isomer.

The maleic acid salt (1:1) of asenapine is known to be therapeutically useful and is commercially marketed for the treatment of schizophrenia and acute manic or mixed episodes associated with bipolar 1 disorder. Asenapine maleate exhibits high affinity and potency for blocking dopamine, serotonin, α-adrenergic and histamine receptors, and no appreciable activity at muscarinic and cholinergic receptors. The rank order of receptor affinity for asenapine maleate reveals a unique human receptor binding signature, characterized by strong serotonergic properties, when compared to other antipsychotic drugs. In the United Stated, asenapine maleate is marketed under the name Saphris™. In Europe, asenapine maleate is marketed under the name Sycrest™.
Asenapine was first described in Example IV of U.S. Pat. No. 4,145,434 (“the '434 patent”). The synthetic process was summarized in a flow sheet in the '434 patent (see Scheme 1), while experimental steps were first described in J. Labelled Compd. Radiopharm. 1994, 34, 845-869.

The reduction of enamide (V) as disclosed in the '434 patent is described to be a major bottleneck for the scale-up of the process to commercial production (see Org. Process Res. Dev. 2008, 12, 196-201). This step is carried out by a magnesium/methanol reduction of the carbon-carbon double bound, which gives rise to the formation of the desired trans-lactam trans-(VI) and its undesired cis-isomer cis-(VI) in an unfavorable ratio of approximately 1:4, together with a significant amount of side products (see Scheme 2). During this process, large amounts of extremely flammable hydrogen gas are formed because of the inevitable highly exothermic side reaction of magnesium with methanol. Additionally, there is no control over the rate in which the heterogeneous reaction between magnesium and methanol takes place. Because of the potential danger of the accumulated heat, a calorimetric study of the original process determined the maximum reaction scale to be only about 10-15 Kg (see Org. Process Res. Dev. 2008, 12, 196-201).

Despite of the drawbacks of the original process, Org. Process Res. Dev. 2008, 12, 196-201 describes that all attempts to develop an alternative process for the magnesium/methanol reduction were unsuccessful (e.g. catalytic hydrogenation in the presence of a variety of palladium, platinum, rhodium, ruthenium and iridium catalysts, different ligands and solvents at pressures varying between 1 and 5 bar; use of zinc powder; Birch reduction using lithium in ammonia; use of magnesium in combination with less acidic alcohols like ethanol or propanol). Org. Process Res. Dev. 2008, 12, 196-201 discloses the dosing of magnesium in portions over a solution of enamide (V) as a way to transform the original process into a safer and more efficient process, since only magnesium in combination with methanol was found to be able to reduce the double bound of enamide (V). However, this process requires the use of some equipments that are not conventional at industrial scale, like solid-addition funnels. Another drawback is that, despite of carrying out the addition of magnesium in portions, a very high amount of heat is released after each addition due to the exothermic reaction between magnesium and methanol (see FIG. 2 in Org. Process Res. Dev. 2008, 12, 196-201). Furthermore, despite of the portion-wise addition of magnesium, about two molar equivalents of hydrogen are still released in an uncontrolled manner due to the side reaction between magnesium and methanol. These drawbacks make this reduction process non viable for an industrial production of asenapine due to safety reasons.
European Patent EP 1710241 B1 describes that some of the disadvantages of the process described in the '434 patent, specially the unfavourable trans-(VI)/cis-(VI) product ratio, can be improved by subsequent partial isomerization of the unwanted cis-isomer cis-(VI) into the trans-isomer trans-(VI) using 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), leading to a thermodynamic equilibrium ratio of trans-isomer trans-(VI) to cis-isomer cis-(VI) of 1:2. Isomers can be separated by chromatography over silica gel, and the cis-isomer cis-(VI) can be isomerized again using DBN resulting in a 1:2 mixture of trans-(VI) and cis-(VI), from which the trans-(VI) can be again separated by chromatography. However, after further repetition of this cycle at kg scale, recrystallization of the three combined fractions of the trans-isomer trans-(VI) produced trans-(VI) in an overall yield of only 38% starting from the enamide (V). Moreover this process involves chromatography, normally not easily implemented at industrial scale.
EP 1710241 B1 also describes a process, again based on the reduction of compound (V) with Mg/MeOH, in which the mixture of cis- and trans-lactams cis-(VI) and trans-(VI), can be treated in an alcoholic solution comprising an excess of strong alkaline base thereby producing a mixture of amino acids trans-(VII) and cis-(VII). The ring-opening reaction is described to be stereoselective, resulting in a 10:1 ratio of the trans-isomer trans-(VII) to the cis-isomer cis-(VII). The trans-amino acid derivative trans-(VII) can be isolated and cyclized to give trans-(VI), with preservation of the trans-stereochemistry, but with an overall yield of only 62% from the enamide (V) (see Scheme 3).

Example 8 of the European Patent EP 1710241 B1 also describes an alternative process for the synthesis of the lactam (VI), see Scheme 4. In this example, (5-chloro-2-phenoxyphenyl)acetic acid methyl ester (compound VIIIa) is reacted with methyl formate in the presence of potassium tert-butoxide to give 2-(5-chloro-2-phenoxyphenyl)-3-hydroxyacrylic acid methyl ester (compound IXa, E/Z mixture 9:1), which is directly cyclized with pyrophosphoric acid to obtain methyl 2-chlorodibenzo[b,f]oxepin-11-carboxylate (compound Xa), referred to us 8-chlorodibenzo[b,f]oxepin-10-carboxylic acid methyl ester in EP 1710241 B1, with 85% yield. This compound is then reacted with nitromethane in the presence of tert-butyl-tetramethylguanidine to give methyl 2-chloro-10-nitromethyl-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIa), referred to us 8-chloro-1′-nitromethyl-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylic acid methyl ester in EP 1710241 B1, with a trans to cis ratio of 8:1, which is directly hydrogenated in the presence of a sponge nickel catalyst to give methyl 10-aminomethyl-2-chloro-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIIa), referred to us 11-aminomethyl-8-chloro-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylic acid methyl ester in EP 1710241 B1, which after treatment with potassium tert-butoxide and dimethyl sulphate, is converted into the lactam (VIa) with an overall yield of 81% from compound (Xa), but predominantly corresponding to the undesired cis-isomer (approximately 85:15 ratio with respect to the trans-isomer), being therefore necessary to carry out one of the above described low-yield processes for the conversion of undesired cis-(VI) to trans-(VI).
